The present molecular-level understanding of polymerization and sickling is reviewed for 2 central questions in sickle hemoglobin pathophysiology, viz., what determines when cells sickle, and what determines when cells get stuck. The description of sickling includes the central aspects of the double nucleation mechanism, as well as recent results on the effects of crowding, with an emphasis on the physiological applicability of this fundamental knowledge. In considering when cells get stuck, new measurements of individual fiber stiffness and the processes of depolymerization are also considered. Finally, a fundamental connection is shown between thermodynamics and rheology.